GB2069495A

GB2069495A - Triazoloquinazolinone derivatives

Info

Publication number: GB2069495A
Application number: GB8104493A
Authority: GB
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1980-02-14
Filing date: 1981-02-13
Publication date: 1981-08-26
Also published as: ZA81708B; FI810426L; AU544275B2; EP0034529A1; PT72501A; DK62281A; EP0034529B1; ES509536A0; GR74418B; DK155883B; IE810290L; ATE4211T1; IE50918B1; ES8207177A1; CA1156228A; ES8304133A1; FI69307B; FI69307C; HU182609B; ES499393A0

Abstract

Novel triazoloquinazolinones of the formula <IMAGE> (I) wherein X is selected from the group consisting of hydrogen, halogen, -NO2, methyl, methoxy and -CF3, n is an integer from 2 to 5, R1 and R2 are individually selected from the group consisting of hydrogen and alkyl and hydroxyalkyl of 1 to 5 carbon atoms and taken together with the nitrogen atom to which they are attached form a saturated heterocycle optionally containing another heteroatom and optionally substituted with at least one member of the group consisting of hydroxy, alkyl and hydroxyalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, acyl of an aliphatic carboxylic acid of 1 to 5 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and aryl optionally substituted with a halogen or -CF3 and their non-toxic, pharmaceutically acceptable acid addition salts having antihistaminic and bronchospasmolytic activity and their preparation.

Description

1 GB 2 069 495 A 1

SPECIFICATION Triazol oqu inazol i none derivatives

This invention relates to new triazoloquinazoli none derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general 5 formula 1, X N 1, N 11 N -N 0 wherein (CH2) n - N -"" R 1 1 1\ R 2 X represents a hydrogen or a halogen, e.g. fluorine, chlorine or bromine, atom, or a nitro, trifl uororn ethyl, m ethyl or rn ethoxy radical; n is 2, 3, 4 or 5; and R, and R21 which may be the same or different, each represents a hydrogen atom or a C1-5 alkyl or hydroxyalkyl radical or, together with the nitrogen atom to which they are attached, they represent a saturated heterocyclic ring optionally containing a further heteroatorn and/or optionally being substituted by one or more substituents selected from hydroxy, C1-5 alkyl, Cj_, hydroxyalkyl, C3-6 cycloalkyl, Cl-, acyl, C2-6 alkoxycarbonyl and aryl radicals (said aryl radicals themselves being optionally substituted by a halogen atom or a trifluoromethyl radical); and acid addition salts thereof.

When R, and/or R2 represents a C,-5 alkyl radical, this may, for example, be a methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl or pentyl radical. When R, and/or R2 represents a C,-, hydroxyalkyl radical, this may, for example, be a hydroxypropyl, hydroxybutyl, hydroxypentyl or preferably a hydrox)fethyl radical. When R, and R21 together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring this may, for example, be a pyrrolidino, piperidino, morpholino or piperazino ring. Substituents which may optionally be present on the heterocyclic ring include, for example, hydroxy, methyl, ethyl and hydroxyethyl radicals; C3-6 cycloalkyl radicals such as e.g. cyclopropyl and cyclohexyl radicals; formyl, acetyl, carbamoyl, thiocarbarnoyl, Cl-, mono- or dialkyl-carbamoyl or - thiocarbamoyl and Cl-, alkylsulphonyl radicals; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl radicals; and aryl radicals such as phenyl radicals.

The compounds of general formula I may form acid addition salts with mineral or organic acids, for example, hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, acetic, formic, propionic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acid, alkanesulphonic acids e.g.

methanesu [phonic or ethanesulphonic acid, arylsulphonic acids e.g. benzenesulphonic orp toluenesulphonic acid or ary1carboxylic acids such as benzoic acid. Such acid addition salts may contain more than one acid moiety and, for example, dihydrochlorides may, be obtained.

The compounds of general formula I and their acid addition salts possess interesting pharmacological properties and in particular, in general, an antihistaminic and bronchospasmolytic 35 activity.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible acid addition salts but other acid addition salts may find use, for example, in the preparation of compounds of general formula I and their physiologically compatible acid addition _40 salts.

Preferred compounds according to the invention are those wherein X represents a hydrogen atom or a methyl or nitro radical; n is 3, 4 or 5; and R, and R2, together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring optionally containing a further heteroatorn and/or optionally being substituted by one or more substituents selected from hydroxy, C,-, cycloalkyl, C2-6 alkoxycarbonyl, phenyl and halophenyl radicals. Of these preferred compounds, more preferred are 45 those wherein X represents a hydrogen atom or a methyl radical and R, and R21 together with the nitrogen atom to which they are attached, represent a 4-phenyl pipe razin- 1 -yl, 4-(chlorophenyl) piperazin-1 -yl or 4-(ethoxycarbonyl)-piperazin-1 -yl radical.

Particularly preferred compounds according to the invention are the following:

1-14-[4-(m-chlorophenyl)-piperazin-1 -yI1-butyl)-[1,2,41triazoIo[6,1 blquinazolin-5(1 H)-one 50 1-14-[4-(ethoxycarbonyl)-piperazin-1 -yI1-butyIj-[1,2,4jtriazolo[5,1 - blquinazolin-5(l H)-one 1-14-[4-(ethoxycarbonyl)-piperazin-1 -yIj-butyIj-7-methyI(1,2,41 triazolo [5,1 -blquinazolin-5(H)- (I) one one 1-13-[4-(ethoxycarbonyi)-piperazin-1 -y11propyl 1-7 -methyl[ 1,2,41tri azolo [5,1 -blquinazolin5(1 H)- GB 2 069 495 A 2 and acid addition salts thereof, especially the dihydrochloride.

The compounds of general formula 1 may, for example, be prepared by the following process which process constitutes a further feature of the present invention: Reaction of a compound of formula 11, I (CH 2)n - Hal r - X -x ' N // 0 (wherein X and n are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) 5 with a compound of formula III, H-N (wherein R, and R2 are as hereinbefore defined.

R, R2 (111) The reaction may, for example, be effected by heating the reactants together, e.g. for about 15 hours at about 1 1WC, in the presence of an inert solvent such as, e.g. dimethylformamide. A condensation agent such as, for example, pyridine or triethylamine may be added if desired.

The compounds of general formula 11 are novel compounds which, together with processes for their preparation, constitute a further feature of the present invention.

formula IV, Compounds of general formula 11 may, for example, be obtained by treatment of a compound of N 1 0 (CH 2) n-011 (TV) (wherein n is as hereinbefore defined and X is as hereinbefore defined, preferably a hydrogen or halogen atom or a trifluoromethyl, methyl or methoxy radical) with a halogenating agent e.g. a phosphorus halide or thionyl chloride, preferably under reflux in the presence of an inert solvent for example a halogenated hydrocarbon such as e.g. clichloroethane or an ether solvent such as e.g. tetrahydrofuran.

The compounds of general formula IV, which are also novel compounds and constitute a further feature of the invention, may themselves be obtained, if desired, by reaction of a compound of formula V, l:H - (CH -OH N- 2)n 2 0 (11) (wherein X and n are as hereinbefore defined) with a formylating agent whereby the desired compound 25 of formula W is obtained. A preferred formylating agent is dimethylformamide dimethyl radical or diethyl acetal, preferably used in the presence of a hydrocarbon solvent e.g. toluene and preferably under reflux. An acid agent such as for example p- toluenesulphonic acid is also desirably present.

Other formylating agents which can be used include, for example, trimethyl orthoformate, triethyl 30 orthoformate, formic acid and dimethy[formamide in conjunction with a suitable acid chloride e.g. benzoyl chloride. Care must, however be taken to avoid side reactions with the side chain alcohol group.

The compounds of general formula V, which are further novel compounds forming a yet further feature of the present invention, may in turn be prepared, for example, by reaction of a compound of formula V] 1 GB 2 069 495 A 3 N11 N H2 - c-,,"1,. 0 lN '1-1 NH 2 (wherein X is as hereinbefore defined) with a compound of formula Vil, NH,--(CH,),,-OH (wherein n is as hereinbefore defined) preferably at elevated temperature e.g. about 1 60'C when 5 reaction is generally complete in about three days.

The compounds of general formula 11 may alternatively be prepared, if desired, by reaction of a compound of formula Vill, N11 X - '11 0 j ',N 5 0 (wherein X is as hereinbefore defined) with a compound of formula IX, (VI) (VI0 (Vili) Hal,-(CHA,-Hal, OX) 10 (wherein n is as hereinbefore defined and Hall and Hal2 which may be the same or different, each represents a chlorine, bromine or iodine atom).

Thus, for example, when Hal in the desired compound of formula 11 represents a chlorine atom, the compound of formula IX is preferably a bromo-chloro-alkane i.e. one of Hal, and Hal2 represents a bromine atom and the other a chlorine atom. The reaction is preferably effected in the presence of a base such as for example sodium hydride or potassium carbonate, potassium carbonate most preferably being used in the presence of a solvent such as acetone and under reflux.

[1,2,4]triazolo[5,1 -b]quinazolin-5(l H)-one (i.e. formula Vill where X represents a hydrogen atom) has been described in J. Chem. Soc. Perkin fl. 1979, 420. The remaining compounds of general formula 20 Vill are, however novel compounds which constitute a further feature of the invention.

The compounds of general formula Vilf may be obtained, for example, by treatment of a compound of formula X, N 0 (wherein X is as hereinbefore defined) with an alkaline agent, for example, an alkali metal hydroxide 25 e.g. sodium or'potassium hydroxide, preferably 0.5M sodium hydroxide.

The compounds of general formula X are still further novel compounds which form another feature of the present invention. They may be prepared, if desired, by reaction of a compound of formula Xl, 112 X _C N>r N1IN L ',5 01 (XI) (wherein X is as hereinbefore defined) with a formylating agent whereby the desired compound of formula X is obtained. A preferred formylating agent is dimethy1formamide and a halide of a weak 30 carboxylic acid, for example an acid having a pka greater than or equal to 4 such as an acetyl or benzoyl halide, e.g. benzoyl chloride. In this case the reaction is preferably effected under reflux. When X represents a nitro radical then the formylating agent is preferably trimethyl orthoformate. Other formylating agents may also be used provided that they do not enter into side reactions with other parts of the molecule.

4 GB 2 069 495 A The compounds of general formula I may, if desired, be converted into their acid addition salts by reaction with an acid preferably in stoichometric quantities. If desired, these acid addition salts may be prepared directly from bases obtained in the above-described process without isolation of the base.

The compounds of general formula VI, when they are not known, may be prepared by the action of hydrazine hydrate on a 2-alkoxy-3-alkyl-quinazolin-4(3H)-one obtained as described in U.S. Patent Specification No. 3,755,582. The compound of formula XI wherein X represents a nitro radical may be obtained by reacting hydrazine hydrate under mild conditions with a solution of 2-chloro-4-hydroxy quinazoline previously treated with a sulpho-nitrating mixture. The remaining compounds of general formula XI may be obtained by treating an appropriate 2-chloro-4(3H)- quinazolinone described for example, by Hess in J. Med. Chem. January 1968, vol 11, p 135, under mild conditions with hydrazine 10 hydrate. The compounds of general formula III wherein R, and R2. together with the nitrogen atom to which they are attached, represent a piperazino ring substituted by a C3- 6 cycloalkyl radical, when they are not known, may be prepared by reaction of 1 -be nzyl pipe razine with a halide of the appropriate cycloalkane followed by removal of the benzyl group, preferably by catalytic hydrogenation.

The preparation of starting materials is illustrated in the Examples.

As mentioned above, the compounds of general formula I and their acid addition salts possess interesting pharmacological properties. Those compounds which we have tested exhibit remarkable antihistaminic and bronchospasmolytic activities. Such compounds are thus of use in the treatment of asthma, bronchitis and allergic disorders.

Their pharmacological activity was illustrated as follows:

Pharmacological Study A) Effects on histamine-induced bronchoconstriction in anaesthetised guinea pigs Male guineapigs weighing 300-400 grams, after overnight starving, were anaesthetised with urethane (0.7 mi/1 00 g) i.p. The preparation was as described by Konsett and Rossler with a ventilatory 25 pump stroke volume varying between 4-6 mi of air (adjusted to each animal) at a stroke rate of 80 a 25 minute to maintain lung inflation pressure of 7.5 em of H 20' Blood pressure was measured via a cannula in the right carotid artery connected to a Statham blood pressure transducer and a Devices M2 recorder. Drugs were administered via the cannulated left jugular vein and washed in with 0. 1 mi of 0.9%.W/' NaCI in distilled water. The test product was administered immediately before the histamine which 30 was used as the agonist.

Respiratory changes were recorded via a differential transducer connected to an SE 905 transducer/converter which in turn was connected to a Devices M2 recorder.

Ref. Konzett, H. and Rossler, R. Arch. exp. Path. Pharmakol (1940) 119571.

The results given in Table 1 show the effective dose of each of the test compounds required to reduce the histamine-induced constriction in lung air volume by 50%.

GB 2 069 495 A 5 TABLE 1

Product of Example -t, 2 3 4 5 6 ED,,, (mg/kg) 0.02 OX08 0.3 7 8 11 12 24 34 0.9 0.03 0.3 2.0 0.1 0.05 1.0 0.05 0.7 0.01 In table 1 it can be seen that the product of Examples 1 and 2 and the product of Example 3 were very effective in antagonising the bronchoconstricting activity ofhistamine.

B) Effect on isolated guinea pig tracheas Guinea pigs were killed by a blow on the back of the neck and the tracheas were excised, cut 5 spirally and suspended in Krebs Henseleit solution at 370C and aerated with 95% 02 + 5% C02, Histamine was used as the agonist.

The following Table 2 shows the amount of each test compound required to reduce the histamine induced contraction of the guinea pig trachea by 50%.

Product of Example TABLE 2

4 6 24 EC,,, (jig/mi) 0.1 34 10.2 0.25 16 36 The product of Examples 1 and 2 was a potent antagonist of histamine- induced contractions; its antagonistic effect was very prolonged and could be demonstrated for up to 30 mins after the compound had been washed out.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula 1 as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

GB 2 069 495 A 6 For pharmaceutical administration the compounds of general formula I and their physiologically compatible acid addition salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral (including topical) administration. Preferred forms include, for example, plain tablets, coated tablets, gelatin capsules, granules, aerosols, suppositories and solutions e.g. for injection.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 1 to 1000 mg, preferably from 1 to 500 mg of active ingredient. The oral daily dosage which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 1 to 1000 mg per day in adults.

The following non-limiting examples serve to illustrate the present invention.

EXAMPLE 1

1-14-[4-(m-chlorophenyi)piperazin-1 -yil-butyll-triazolo [ 1,2,41[5,1 -blquinazolin-50 H)-one dihydrochloride Step A 3-amino-2-(4-hydroxybutylamino)-quinazolin-4(3H)-one 3-Amino-2-hydrazinoquinazolin-4(3H)-one (16 g) is stirred in 4aminobutanol (48 m]) at 1600 for 3 days. The bulk of the 4-aminobutanol is then distilled off under vacuum and the residue is diluted with water. The resultant mixture is seeded and then stored at 01 overnight to crystallise out the product which is filtered off, washed and dried. Yield 12.05 g.

Step B 1-(4-hydroxybutyl)-triazolo[1,2,41[5,1-bl-quinazolin-5(1H)-one A mixture of 3-amino-2-(4-hydroxybutylamino)-4(3H)-one (23 g), dimethylformamide dimethyl acetal (15 g) and ptoluenesulphonic acid (2 g) is refluxed in dry toluene (230 mi) until evolution of dimethylamine ceases (about 8 h). The product crystallises out on cooling and is filtered off, washed with ether and dried. Yield 22.8 g.

StepC 1-(4-chlorobutyl)-triazolo[I.2,41[5,1-blquinazolin-5(1H)one The hydroxy compound prepared in step B (23 g) is stirred with thionyl chloride (13.5 mi) in dry dichloroethane (500 mO under reflux for 6% hours, whereupon fl.c. shows the reaction to be complete.

The mixture obtained is cooled and stirred with an equal volume of aqueous sodium carbonate until solid material dissolves.

The organic layer is separated, dried (M9S04) and concentrated to 100 m] whereupon the product 35 starts to crystallise out. Ether (100 mi) is added thereto and the resultant mixture is cooled. The product thus formed is filtered off, washed with ether and dried. Yield 22.5 g.

Step D 1- 14- [4-(m-ch loro phenyl) piperazin- 1 -Vil-butyll-triazolo[1,2, 41[5,1 -blquinazolin-5(1 H)-one di hydrochloride A mixture of the chloro compound from step C (23 g) and 1-(m- chlorophenyi)piperazine (25 g) in 40 dimethy[formamide (400 mi) is heated at 1101 for 15 hours, cooled and then diluted with chloroform (1.5 1). The chloroform solution is washed three times with water, dried (M9S04) and stripped of solvent under reduced pressure. The residue is dissolved in methanol and the solution obtained is treated with a solution of hydrogen chloride in ethyl acetate to precipitate the hydrochloride salt of the product, which product is then filtered off and washed with methanol. The crude product is purified by refluxing in 45 methanol (1 1). The mixture obtained is cooled and the product filtered off. Yield 31.5 g.

The 3-amino-2-hydrazinoquinazolin-4(3H)-one may be prepared according to one of the following methods:

3-methyi-2-thioquinazolin-4(3H)-one (German OLS 2539396), 2-chloro-4hydroxyquinazoline Q.

Chern Soc 1947,775) or2-hydrazino-4-hydroxyquinazoline (Bull,SocChern Beige 1959,68,2200s 50 stirred in hydrazine hydrate (5 vol) under reflux evolution of amine has ceased (ca 5 hour). The resultant mixture is allowed to cool a little, diluted with water (5 vol) and then cooled to room temperature. The product obtained is filtered off, washed with water and then with methanol and dried. Yield of 3-amino 2-hydrazoquinazolin-4(3H)-one 70-75%.

The 2-chloro-4-hydroxyquinazoline may bre prepared according to the following reactions:

a) Isatoic anhydride (978 9) is added in portions to a stirred mixture of urea (720 g) and dimethylformamide (1 1) at 1501. The temperature is raised to 180' until evolution of ammonia has ceased then the mixture obtained is allowed to cool. Water (1 1) is added as soon as possible to the cooling mixture followed by methanol (1 1). The warm resultant mixture is stirred for 1 hour and then the quinazolin-2,4-dione obtained is filtered off and washed with warm water and methanol.

Purification is carried out by stirring tne product in 2-3 volumes of warm dimethylformamide, 7 GB 2 069 495 A 7 filtering and washing with methanol. Yield 747 g.

b) A mixture of quinazoline-2,4-dione (300 g), N,N-dimethylaniline (150 mi) and phosphoryl chloride (1 1) is refluxed for 51 hours, cooled a little and poured with vigorous stirring onto crushed ice. The ice-cold 2 resultant mixture is filtered and the product obtained is washed acidfree with iced water. The wet product thus obtained is stirred into aqueous sodium hydroxide (2N, 2.25 1) and the resultant mixture is stirred until a clear solution is obtained (ca 3 hours).

The solution is filtered and the filtrate is neutralised with glacial acetic acid to precipitate the product which is then filtered off, washed with water and dried. Yield of 2-chloro-4-hydroxyquinazoline 263 g.

2-Chloro-4-hydroxyquinazoline (134 g) is stirred in hydrazine hydrate (670 mi) under reflux until 10 evolution of ammonia has ceased (ca 5 hours). The resultant mixture is allowed to cool a little, diluted with water (670 mi) and then cooled to room temperature. The product obtained is filtered off, washed with water and then with methanol and dried. Yield of 3-amino-2-hydrazinoquinazolin- 4(3H)-one 101.5 g.

EXAMPLE 2 1-14-[4-(m-chlorophenyi)-piperazin-1 -yil-butyll-triazolo-[1,2, 41[5,1 -blquinazolin-5(1 H1l-one dihydrochloride Step A triazolo[1,2,4j[3, 4-blquinazolin-5(1H)-one 2-Hydrazino-4-hydroxyquinazoline (10 g) is added to a stirred solution of benzoyl chloride (20 g) in dimethylformamide (40 mi). The mixture obtained is refluxed until a clear solution is obtained and then 20 poured into water. The product thus precipitated is filtered off, washed with water and methanol and dried. Yield 8 g.

Step B triazolo[1,2,41[5, 1-blquinazolin-5(1H)-one The triazolo[1,2,41[3,4-blquinazolin-5(1 H)-one obtained in step A is stirred at 901 in aqueous sodium hydroxide (1 mole, 0.5N) until t.l.c. shows the reaction to be complete. The resultant solution is 25 cooled and then acidified with acetic acid. The product thus precipitated is filtered off, washed with water and methanol and dried. Yield 100%.

Step C 1-(4-chlorobutyl)[1,2,4]triazolo[5, 1 -bjquinazo#n-5(1H)-one The [1,2,4]triazolo[5,1 -b]quinazolin-5(l H)-one obtained in step B is alkylated with 4- bromochlorobutane using either sodium hydride/dmf orrefluxing acetone/potassium carbonate. In both 30 cases a mixture of 1 and 3- substituted products is obtained which are separated on an alumina column. The 3-isomer is eluted with chloroform - 60/80 petrol(1:1) and then the 1 -isomer with chloroform. Yield of 1 -isomer 20-30%.

Step D 1-14-[4-(m-chlorophenyl)-piperazin-l-yll-butyll-[1,2,4]triazolo[5, 1-blquinaz olin-5(1H)-one dihydrochloride A mixture of 1-(4-chlorobutyi)-[1,2,4]triazolo[5,1 -blquinazolin-5(1 H)- one (23 9) obtained in step C and 1 -m-chlorophenylpiperazine (25 g) in dimethylformamide (400 mi) is heated at 1101 for 15 hours, cooled and diluted with chloroform (1.5 1). The chloroform solution is washed three times with water, dried (M9S04) and stripped of solvent under reduced pressure.

The residue is dissolved in methanol and the solution obtained is treated with a solution of hydrogen chloride in ethyl acetate to precipitate the hydrochloride salt of the product which is then filtered off and washed with methanol. The crude product is purified by refluxing in methanol (1 1). The resultant mixture is cooled and the product is filtered off. Yield 31.5 g.

EXAMPLE 3

1-14-[4-(ethoxycarbonyi)piperazin-1 -yilbutyll-7-methyi-[1,2,4]triazolo[5, 1-b]quinazolin-5(1 H)-one 45 dihydrochloride Step A 3-amino-2-(4-hydroxybutylamino)-6-methylquinazolin-4(3H)one 3-Amino-2-hydrazino-6-methyiquinazolin-4(3H)-one (20 g) is stirred in 4aminobutanol (100 mi) at 1751 for 24 hours. The bulk of the 4-aminobutanol is then distilled off under vacuum and the residue is diluted with water to crystallise out the product which is filtered off, washed and dried. Yield 16.2 g. 50 Step B 1-(4-hydroxybutyl)7-methyl[1,2,4]triazolo[5, 1-blquinazolin-5(1H)- one A mixture of 3-amino-2-(4-hydroxybutylamino)-6-methylquinazolin-4(3H)-one (15 g), dimethylformamide dimethyl acetal (10 g) and p-toluenesulphonic acid (1.5 9) is refluxed in dry toluene (250 nil) until evolution of dimethylamine ceases (about 24 h). The product crystallises out on cooling and is filtered off, washed with ether and dried. Yield 14 9.

Step C 1-(4-chlorobutyl)-7-methyl[1,2,4]triazolo[5,1-blquinazolin-5(1H)one The hydroxy compound prepared in step B (12 9) is stirred with thionyl chloride (12 mi) in 8 GB 2 069 495 A 8 chloroform (500 mO under reflux for 20 hours whereupon fl.c. shows the reaction to be complete. The hot mixture is stirred with an equal volume of aqueous sodium carbonate until solid material dissolves. The organic layer is separated, dried (M9S04) and evaporated to dryness to give the product which is filtered off, washed with ether and dried. Yield 8.8 g.

Step D 114-[4-(ethoxycarbonyl)piperazin-l-yllbutyll-7-methyl[1,2, 4]triazolo[5,l-blq uinazolin5(1H)- 5 one dihydrochloride A mixture of the chloro compound from step C (8 9) and ethyl piperazine-l- carboxylate (8 g) in dimethylformamide (20 mi) is heated at 1000 for 8 h. and then diluted with chloroform (50 mi). The chloroform solution is washed three times with water, dried (M9S04) and stripped of solvent under reduced pressure. The residue is dissolved in methanol and the solution obtained treated with concentrated hydrochloric acid (8 mi) to - preci " pitate the hydrochloride salt of the product which is then filtered off, washed with methanol and dried. Yield 7.6 g.

The 3-a m ino-2-hydrazino-6-m ethyl qu inazol in-4(3 H)-one may be prepared according to the following method:

2-mercapto-3,6-dimethyiquinazolin4(3H)-one,2-chloro-6-methylquinazolin-4o1,2-hydrazino-6- 15 _# methylquinazolin-4-ol or 2-merca pto-6-m ethyl quinazolin-4-ol is stirred in hydrazine hydrate (5 vol) under reflux for 24 h. The resultant mixture is diluted with water (5 vol) and cooled to room temperature. The product obtained is filtered off, washed with water and then methanol and dried. Yield of 3-amino-2hydrazino-6-methyiquinazolin-4(3H)-one 95%.

EXAMPLES4-42

Using a method analogous to that described in Example 1 of the products indicated in the following Table were prepared.

2-hydrazino-4-hydroxy-6-nitroquinazoline may be prepared according to the following method:

Step A 2-chloro-4-hydroxy-6-nitroquinazoline A cooled mixture of concentrated sulphuric acid (70 mi) and concentrated nitric acid (35 mi) is 25 added dropwise into a cooled, stirred solution of 2-chlorc-4hydroxyquinazoline (90 g) (J. Chem. Soc.

1947 775) in concentrated sulphuric acid (270 mi) at a rate such that the temperature remains at 5-101. Stirring is continued until the reaction mixture reaches room temperature, whereupon it is poured onto crushed ice. The product thus precipitated is filtered off, washed well with water and used directly in the next step.

Step B 2-hydrazino-4-hydroxy-6-nitroquinazoline The wet product from the previous step is dissolved in a mixture of hydrazine hydrate (90 m[) and water (900 mO and the mixture obtained is stirred at 90-1000 until crystallisation takes place. The resultant mixture is allowed to cool and the hydrazino compound is filtered off, washed with water and 35 35 methanol and dried. Yield 97.2 g of a high melting, orange crystalline solid.

9 GB 2 069 495 A 9 Example

X H 7-Me H H H H H H 7-NO, n 4 4 4 4 3 3 3 3 4 -N RI R, Formula 1,2 3 4 6 7 8 9 - /-\_00 c -i 1 -N N - CO 2 EL H -N -N -N \--7 -CO -10 PH -UO N CH 2 -CH cH 2-H2-011 f-\ cl C,^, N,OC 1, 2HC I, H20 C,,H28N,O, MC I. Y2H20 0141-127N, 0, 21-IC I,H,0 C,.,H3,N,0.2HCI C2,1-1,,N,0C1, 21-IC I. 2H20 C,H2,N, 0, 21-IC 1, 1/21-1,0 C23H2, N, 02, MC 1 C161-121N,021 21-ICI, 1/21-1,0 C2,1-124N703c 1 GB 2 069 495 A 10 Example

11 12 13 14 16 17 18 19 X n -N R 1 R,.

Formula H H 7-NO2 H H H H H H 3 3 4 4 4 4 4 N f---\ C: cl - N - 110 1 " co 2 E t N N -CO 2 Et N N - CO Pr 2 l \--7 - CO 2 Bu 14 NI - CO 2 isOBU N P1 -1.1e 024H2.,N,OC 1, 21-ICI, M/21-1,0 C,,H2, N, 0, 2HCl, 1A/2H,.0 C22H22N,O,C 1, HCl C,H24N,0, 2HCI.H,0 C2,,1-126N603 2HCl 1-1,0 C211-12.bl,0, 21-IC 1. 112 H20 C22H3,N603 21-ICI, 1/2 1-1,0 C22H3,,N,10, 21-IC 1, 112 H20 C,H2M0 21-ICI, 2H20 11 GB 2 069 495 A 11 Example

21 X H H H 7-Me H 7-Me 7-Me 7-Me 7-Me n 4 4 4 4 4 4 4 4 4 -N -" R, R, Formu la CH 011 N4 14 - CH2 2 /--I\i - CHO 22 23 24 26 27 28 C,^,N602 MCI, 112 H20 C,,H22N602 21-IC1 0/-u \t, \--/ _co cl N n\ - C 0 2 Pr N -CO isoBu \ -j 2 1 -- 4 -cii 2 cl] 2 OH -i C17H2,N60 MC 1 C24H2.,N,OC 1 21-ICI, HP C,,1-12M0, MC I. H,0 C22HUNP3 21-IC1 C2,1-132N601 MCI, 1/2 H20 C,H26N60 31-IC 1, 1.1 /2 H20 C,,,H2aN602 MCI, 1/2 H20 12 GB 2 069 495 A 12 Example 29 31 32 33 X 7-Me 7-Me 7-Me 8-C 1 8-cl 7-Me H H H n 4 4 4 4 4 3 4 4 4 -N

R, R Formula N- CHO \-j Imn, 11 2 N 11 - COCII 3 -i I/--\---co 1 j N 01 CO 2 Et 34 1 36 37 C,H24N602 C19H2M0 MC I, H.,0 C2,^ 6N 602 21-ICI, 1A/2 H20 C,,]-12,1\1,0C12 21-IC1 c 2oH,, N,O,C 1 HC 1. 112 H20 N N-CO 2 Et N N-CMEt 2 N NCON11Me N N-CON1IEt OW,H26N603 MC 1 C2AIN702 21-IC I, H20 C,,H2, N702 21-IC 1 C2,H2,N,0, 13 GB 2 069 495 A 13 Example X n -N Formula 1-1 R, 38 H 4 N N-CS NHtle C,^, N,0S 2HCl, 1/2 H,0 39 H 4 N N-S02Me C,,H24N603S 2HC 1 H 4 N N-CO Me C,1-124N603 2 2HC 1 41 7-Me 4 N N-C0214e c 2oH26N60, 2HCl. 1/2 H 20 42 H 4 N N c 1 C2,1-12,1\160 Cl 31-IC 1, 1/3 H20 14 GB 2 069 495 A 14 Examples 1,2

3 4 Analysis Cal cu fated/ Found Recrystal I isati on C% H%, Cl% I N% M.P. C Solvent 52.33 5.57 19.67 15.92 222-5 methanol 52.2 5,5 19.7 15.9 51.01 6.32 17X0 228-30 50.6 6.3 16.9 6.15 13.95 13.77 221-3 ethyl acetate/ 6.1 13.8 13.9 methanol 223-50 49.68 5.45 20.00 15.79 237-8 ethanol 49.3 5.4 19.6 15.7 51.91 6.10 18.03 17.80 245-70 ethyl acetate/ 51.9 6.0 17.8 methanol 57.99 5.71 14.88 14.70 2100 ethyl acetate/ 57.7 5.8 14.7 methanol 48.36 6.08 17.84 17.62 170-5 ethyl a,-etate/ 48.3 5.6 17.6 methanol 186-90 52.32 5.86 19.30 15.25 226-8 ethyl acetate/ 52.3 5.9 18.5 15.5 methanol 51.93 6.88 16.14 15.94 216-80 ethyl acetate/ 52.0 6.7 15.4 16.3 methanol 52.39 4.59 14.06 19.44 275 52.3 4.5 14.1 19.1 (decomp) 48.01 5.94 14.92 17.68 222-40 47.9 5.6 14.5 17.6 (decomp) 49.07 6.19 14.49 17.17 234-5' 49.0 5.8 14.5 17.1 (decomp) 51.02 6.32 14.34 17.00 230-20 ethyl acetate/ 51.0 6.3 14.2 17.0 (decomp) methanol 51.97 6.54 13.95 16.53 230-2 c ethyl acetate/ 51.6 6.6 13.5 16.5 (decomp) methanol 51.97 6.54 13.95 16.53 230-20 ethyl acetate/ 52.2 6.5 14.0 16.7 (decomp) methanol 48.11 6.73 15.78 18.70 235-70 47.6 6.6 15.9 18.4 46.68 6.19 21.76 17.19 235-70 46.3 5.9 21.1 17.0 218-200 (decomp) 6 7 8 9 11 12 13 14 16 17 18 19 21 Examples 22

23 24 26 27 28 29 31 32 33 34 36 37 38 39 41 42 GB 2 069 495 A 15 Analysis Calculated/Found C% 53.48 53.5 51.93 52,0 52.87 529 46.50 46.9 47.77 47.7 61.21 61.0 46,20 46.1 50.00 50.1 50.74 50.5 50.25 50.7 50.96 50.9 51.16 51.2 49.18 48.9 47.40 47.1 42.86 43.0 50.00 50.1 50.02 50.2 1-1% 5.25 5,7 6.53 6.0 6.70 6.5 6.57 6.5 6.42 6.1 6.58 6.5 6.26 6.3 6.04 5.9 4.78 4.8 5.69 5.7 6.00 6.0 6.83 6.4 6.40 6.3 5.86 5.6 5.79 5.7 6.04 5.9 5.23 5.2 Cl% 19.73 19.0 17.03 16.2 13.60 13.3 26.10 26.1 15.04 15.0 13.73 14.5 14.73 15.1 14.06 14.1 25.67 25.4 N% 15.60 159 16.82 17.1 16.09 16.1 17.12 17.4 16.71 16.7 22.55 22.5 17.97 18.0 17.50 17.6 15.44 15.5 17.57 17.6 17.83 17.9 18.98 19.2 20.07 20.0 20.37 19.9 16.66 16.9 17.50 17.6 15.22 15.4 Recrystallisation M.P. OC Solvent 220-20 ethyl acetate/ decomp) methanol 216-9 23,1-5 ethyl acetate/ methanol 244-60 ethyl acetate/ methanol 240-20 244- 61 225-70 (Analysis for free base) 250-30 227.30' ethyl acetate/ methanol 235-70 233-5 226-80 ethyl acetate/ decomp) methanol 226-70 decomp) 203-5-1 decomp) 212.5' decomp) 185-7 decomp) 220-20 (Analysis for +11/2 decomp) H,O) ethyl acetate/ methanol 2150 decomp) 222-5' ethyl acetate/ methanol 230-1o decomp) 16 GB 2 069 495 A 16 EXAM P LE A Tablets were prepared according to the formulation:

1-14-[4-(ethoxycarbonyi)-piperazin-1 -yI] -b utyl 1-7-m ethyl[1,2, 4]triazoio[5,1 -bjquinazolin-5(1 H)-one dihydrochloride Excipient q.s. for one tablet up to (Details of the excipient: lactose, starch, talc, magnesium stearate).

EXAMPLE B

Tablets were prepared according to the formulation:

1 -1 4-[4-(ethoxyca rbonyi)-piperazin- 1 -yil -butyl 1-7-m ethyl[1,2,41--triazolo[5,1-blquinazolin-5(1H)-onedihydrochloride Excipient q.s. for one tablet up to (Detail of the excipient: lactose, starch, talc, magnesium stearate).

EXAMPLE C

A dosed aerosol was prepared delivering per dose:

1-14-14-(ethoxycarbonyi)-piperazin-l-yil-butyll-7-methy][ 1,2, 4]triazolo[5,1 -blquinazolin-5(1 H)-one dihydrochloride Emulsifier Propellant EXAMPLE D

A syrup was prepared according to formulation:

1 - 1 4-[4-(ethoxycarbonyi)-piperazin- 1 -yi]-butyl 1-7 -methyl [ 1,2,4]triazolo[5,1 -blquinazolin-5(1 H)-one Odoring and sweetening excipient qsp

Claims

25, 1. Compounds of general formula 1, wherein mg 0 mg 5 mg 1() 10Orng 2 mg 0.15 mg mg 0.3 g m] I x__O 1:

0 (CH2) n - m _,- R 1 R 2 (1) X represents a hydrogen or a halogen atom or a nitro, trifl uoro m ethyl, methyl or methoxy radical; n is 2, 3, 4, or 5; and R, and R21 which may be the same or different, each represents a hydrogen atom or a C1-5 alkyl or 30 hydroalkyl radical or, together with the nitrogen atom to which they are attached, they represent a saturated heterocyclic ring optionally containing a further heteroatom and/or optionally being substituted by one or more substituents selected from hydroxy, Cl-, alkyl, C1-5 hydroxyalkyl, C3-6 cycloalkyl, Cl-, acyl, C2-6 alkoxycarbonyl and aryl radicals (said aryl radicals themselves being optionally substituted bya halogen atom oratrifluoromethyl radical); and acid addition salts thereof.
2. Compounds as claimed in claim 1 wherein X represents a hydrogen atom or a methyl or nitro radical; n is 3, 4 or 5; and R, and R21 together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring optionally containing a further heteroatorn and/or optionally being substituted by one or more substituents selected from hydroxy, C,_, cycloalkyl, C2-6 alkoxycarbonyl, phenyl and halophenyl radicals.
3. Compounds as claimed in claim 2 wherein X represents a hydrogen atom or a methyl radical and R, and R21 together with the nitrogen atom to which they are attached, represent a 4phenylpiperazin-1 -yl, 4-(ch lorophe nyl) -pipe razi n- 1 -yl or 4-(ethoxycarbonvl)-ninerazin-1 -yI radical
4. 1-14-[4-(m-Chlorophenyi)-piperazin-l-yil-butyil-[1,2,4]triazolo[5,1b]quinaz oiin-5(1H)-one and 45 acid addition salts thereof.

j 17 GB 2 069 495 A 17
5. 1-14-[4-(Ethoxycarbonyi)-piperazine-1 -yi]-butyil-[1,2,4]triazolo[5,1 - blquinazolin-5(1 H)-one and acid addition salts thereof.
6. 1 -14- [4-(Rhoxyca rbonyO -p! perazin- 1 -yll-butyl 1-7 -methyl[ 1,2, 41triazolo [5,1 -b] qu in azolin-5 (1 H) one and acid addition salts thereof.
7. 1-13-[4-(Ethoxycarbonyi)-piperazin-l-yllpropyll-7-methyi[1,2, 4]triazolo[5,1-b]quinazolin- 5 W-one and acid addition salts thereof.
8. Physiologically compatible acid addition salts of compounds of general formula 1 as claimed in any preceding claim.
9. The dihydrochlorides of compounds of general formula 1 as claimed in any one of claims 1 to 7.
10. Compounds as claimed in claim 1, other than those claimed in any one of claims 4 to 7, as 10 herein specifically disclosed in any one of Examples 1 to 42.
11. A process for the preparation of compounds of general formula 1 as defined in claim 1 which comprises reacting a compound of formula 11.

N --, -0 N 0 (CH) - Hal
1 2 n (II) (wherein X and n are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a 15 compound of formula 111, H-N (wherein R, and R2 are as defined in claim 1).

R, R2 12. A process as claimed in claim 11 wherein the reactants are heated together for about 15 20 hours at about 11 OIC in the presence of an inert solvent.
13. A process as claimed in claim 11 or claim 12 wherein the reaction is effected in the presence of a condensation agent.
14. A process as claimed in any one of claims 11 to 13 wherein the compound of formula 11 is obtained by treatment of a compound of formula W, N 1 (CH 2)n_011 X -C 0 (wherein X and n are as defined in claim 1) with a halogenating agent.
15. A process as claimed in claim 14 wherein, in the compound of formula W, X represents a hydrogen or a halogen atom or a trifl uoro m ethyl, methyl or methoxy radical.

(IV)
16. A process as claimed in claim 14 or claim 15 wherein the halogenating agent is a phosphorus 30 halide or thionyl chloride.
17. A process as claimed in any one of claims 14 to 16 wherein the treatment is effected under reflux in the presence of a halogenated hydrocarbon or an ether as solvent.

18. A process as claimed in any one of claims 14 to 17 wherein the compound of formula IV is obtained by reaction of a compound of formula V, X 1 1 Z NH - (CH 2)n - OH (V) 35 N-, NH 2 (wherein X and n are as defined in claim 1) with a formylating agent whereby the desired compound of formula IV is obtained.
18 GB 2 069 495 A 18
19. A process as claimed in claim 18 wherein the formylating agent is dimethylformamide dimethyl acetal or diethyl acetal.
20. A process as claimed in claim 18 or claim 19 wherein the reaction with the formylating agent is effected under reflux and in the presence of a hydrocarbon solvent.
21. A process as claimed in any one of claims 18 to 20 wherein the reaction with the formylating 5 agent is effected in the presence of an acid agent.
22. A process as claimed in any one of claims 18 to 21 wherein the compound of formula V is obtained by reaction of a compound of formula VI, Y Nil -0 I- ",V, 11 -- Mil 2 0 (wherein Xis as defined in claim 1) with a compound of formula V11, NH:-(CH2)n-OH (wherein n is as defined in claim 1).

(VI) (V11)
23. A process as claimed in claim 22 wherein the reaction of the compound of formula V1 with the compound of formula V11 is effected at a temperature of about 1 601C for about three days.
24. A process as claimed in any one of claims 11 to 13 wherein the compound of formula 11 is 15 obtained by reaction of a compound of formula Vill, N Nil (wherein X is as defined in claim 1) with a compound of formula IX, Hail-(CH2)n-Hal2 (VIII) OX) (wherein n is as defined in claim 1 and Hall and Hal., which may be the same or different, each 20 represents a chlorine, bromine or iodine atom).
25. A process as claimed in claim 24 wherein the reaction of the compound of formula Vill with the compound of formula IX is effected in the presence of a base.
26. A process as claimed in claim 24 or claim 25 wherein the reaction of the compound of formula Vill with the compound of formula IX is effected in the presence of acetone and under reflux.
27. A process as claimed in any one of claims 24 to 26 wherein the compound of formula Vill is obtained by treatment of a compound of formula X, Nil -J/ N (wherein X is as defined in claim 1) with an alkaline agent.

r X)
28. A process as claimed in claim 27 wherein the alkaline agent is an alkali metal hydroxide. 30
29. A process as claimed in claim 27 or claim 28 wherein the compound of formula X is obtained by reaction of a compound of formula X], N ", NIINTI 2 oil (XI) (wherein X is as defined in claim 1) with a formylating agent whereby the desired compound of formula 35 X is obtained.

1 1 GB 2 069 495 A 19
30. A process as claimed in claim 29 wherein the formylating agent is dimethylformamide and a halide of a weak carboxylic acid.
3 1. A process as claimed in claim 30 wherein the halide of the weak carboxylic acid is an acetyl or benzoylhalide.
32. A process as claimed in claim 29 wherein, in the compound of formula XI, X represents a nitro 5 radical and the formylating agent is trimethyl orthoformate.
33. A process for the preparation of acid addition salts of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula I as defined in claim 1 with an acid,
34. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.
35. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 42.
36. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 11 to 35.
37. Pharmaceutical compositions comprising, as active ingredient, at least one compound of 15 formula I as defined in claim 1 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.
38. Compositions as claimed in claim 37 in a form suitable for oral, rectal or parenteral administration.
39. Compositions as claimed in claim 37 or claim 38 in the form of plain tablets, coated tablets, 20 gelatin capsules, granules, aerosols, suppositories or solutions.
40. Compositions as claimed in any one of claims 37 to 39 in the form of dosage units.
4 1. Compositions as claimed in claim 40 wherein each dosage unit contains from 1 to 1000 mg of active ingredient. 25
42. Compositions as claimed in claim 41 wherein each dosage unit contains from 1 to 500 mg of 25 active ingredient.
43. Pharmaceutical compositions as claimed in claim 37 substantially as herein described.
44. Pharmaceutical compositions substantially as herein described in any one of Examples A to D.
45. Compounds of general formula I as defined in claim 1 and their physiologically compatible acid addition salts for use in the treatment of asthma, bronchitis and allergic disorders.
46. Compounds of general formula 11 as defined in claim 11.
47. A process for the preparation of compounds of general formula 11, as defined in claim 11, as defined in any one of claims 14 to 32.
48. Compounds of general formula IV as defined in claim 14.
49. A process for the preparation of compounds of general formula IV, as defined in claim 14, as 35 defined in any one of claims 18 to 23.
50. Compounds of general formula V as defined in claim 18.
51. A process for the preparation of compounds of general formula V, as defined in claim 18, as defined in claim 22 or claim 23.
52. Compounds of general formula VIII as defined in claim 24 wherein X represents a halogen 40 atom or a nitro, trifluoromethyl, methyl or methoxy radical.
53. A process for the preparation of compounds of general formula Vill, as claimed in claim 52, as defined in any one of claims 27 to 32.
54. Compounds of general formula X as defined in claim 27.
55. A process for the preparation of compounds of general formula X, as defined in claim 27, as 45 defined in any one of claims 29 to 32.
56. Each and every novel method, process, compound and composition herein disclosed.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, Southampton Buildings, London, WC2A lAY, from which copies may be obtained.